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Hints of epigenetic role in Alzheimer’s disease

By Andy Coghlan

BRAIN tissue has yielded the first evidence of an association between Alzheimer’s disease and changes in the way some genes function. But it is not yet clear if the changes lead to the disease or occur as a result of it – or are simply a natural part of ageing.

There is already some evidence that the risk of developing Alzheimer’s rises with poor diet, a lack of exercise and inflammatory conditions such as diabetes. Two independent teams, one in the UK and one in the US, now suggest that these factors can raise the risk by triggering epigenetic changes. Such changes – which may also be brought about by stress – don’t alter the sequence of DNA that someone has inherited. Instead, they affect how genes function. Epigenetic changes have previously been linked to cancer and mental disorders.

Both teams’ work involved screening DNA from the brains of people who had died. The researchers were looking for genes that had been switched off through methylation – the addition of chemical methyl groups to DNA. Between them, they studied samples from about 1000 people, about three-quarters of whom had Alzheimer’s when they died.

Three brain regions particularly affected by the disease were examined&colon; the prefrontal cortex, entorhinal cortex and temporal gyrus.

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In papers published in Nature Neuroscience, the UK team identified seven genes especially affected by epigenetic changes (doi.org/t8t), while the US team found 11 (doi.org/t8s). Four genes were identified by both teams.

The most dramatic methylation differences between brain samples affected by Alzheimer’s and control samples were in a gene called ANK1, which has not previously been linked with Alzheimer’s. That gene codes for ankyrin 1, an ingredient of the outer membranes of cells that is vital for keeping them intact.

“Genetic studies have linked ANK1 to type 2 diabetes, which has links to dementia, so there could be some common pathway linking the two diseases,” says Jonathan Mill at the University of Exeter, who led the UK team. “Given the lack of success tackling Alzheimer’s so far, new leads are going to be vital,” he says. “The results are compelling and consistent.”

The results are compelling. Given the lack of success tackling Alzheimer’s so far, new leads are vital

“We can now focus our efforts on understanding how these genes are associated with the disease,” says Philip De Jager of the Brigham and Women’s Hospital in Boston, who headed the US team.

That might not be so easy. Because the brain samples used in both studies came from people who had died, the researchers cannot say yet whether the gene changes led to the disease or occurred because of it. Indeed, some of the epigenetic effects were as pronounced in those who had shown no symptoms of Alzheimer’s as they were in people who died with the disease.

Mill and De Jager say that the changes seen occur early in the disease, and so at the very least they might be useful for predicting whether or not people are at raised risk of developing symptoms later on. De Jager also points out that methylation is a reversible process, so with the right drugs it might be possible to reverse unwanted epigenetic changes.

This article appeared in print under the headline “Alzheimer’s linked to epigenetics”